Pellet formulations of acid-labile benzimidazonle compounds

Abstract

They comprise insert granules of sugar / starch which are: initially coated with a non-alkaline active layer having the benzimidazole compound (omeprazole, lansoprazole, pantoprazole, rabeprazole, etc.), sodium and / potassium salts of acids of formula R—O—SO3H wherein R is an alkyl radical of a (C6-C20)-fatty acid (preferably sodium lauryl sulfate), (C6-C20)-fatty acids (preferably oleic acid), sodium and / or potassium salts of (C6-C20)-fatty acids (preferably potassium oleate), sodium carboxymethyl starch and polyvinylpyrrolidone; secondly coated with a non-alkaline barrier layer having hydroxypropylmethylcellulose; and finally coated with an enteric layer. The preferred molar ratio (sodium lauryl sulfate):(oleic acid+potassium oleate) is between 4:1 and 6:1. All coatings are done with aqueous solutions, suspensions or dispersions at a relatively high temperature, and all dryings are done at a relatively low temperature and for a relatively short time. They are stable over time and useful for oral administration.

Description

[0001] The present invention relates to new pellet formulations for oral administration of known acid labile benzimidazole compounds, and to a preparation process thereof. BACKGROUND ART [0002] Benzimidazole compounds of formula (I), wherein R1 is selected from the group consisting of hydrogen, methoxy and difluoromethoxy; R2 is selected from the group consisting of methyl and methoxy; R3 is selected from the group consisting of methoxy, 2,2,2-trifluoroethoxy and 3-methoxypropoxy; R4 is selected from the group consisting of hydrogen and methyl are a group of pharmaceutical active ingredients known to be useful for the treatment of gastrointestinal diseases and / or disorders. This group include commercial pharmaceutical active substances such as omeprazole (wherein R1=R3=methoxy; R2=R4=methyl), lansoprazole (wherein R1=R4=hydrogen; R2=methyl; R3=2,2,2-trifluoroethoxy), pantoprazole (wherein R1=difluoromethoxy; R2=R3=methoxy; R4=hydrogen) and rabeprazole (wherein R1=R4=hydrogen; R2=met...

AI Technical Summary

Benefits of technology

[0022] The loading of active ingredient of the pellets of the present invention can be as high as 10% by weight, which is higher than the loading of some pellet formulation known in the art (e.g. the 8.4% of the one described in WO 9325204-A). This feature represents both a shorter manufacturing time and an economic saving in excipients. Another advantage of the present invention over that of WO 9325204-A is the use of water as the only solvent, thus avoiding the more problematic use of ethanol or other organic solvents.

[0023] The preparation process of the pellet formulations of the present invention allows a first active coating at a relatively high temperature of granules (from about 50° C. to about 70° C.), substantially higher than the temperature corresponding to processes known in the art (e.g. 40° C. in EP 237.200-A). It also allows drying at relatively low temperatures (25-35° C.) and / or for short times (20 min), all of which represent manufacturing advantages over other processes known in the art (e.g. 40° C. for 16 h in EP 237.200-A; 50° C. for 4 h in WO 0071121-A).

[0024] Throughout the description and claims the word “comprise” and its variations are not intended to exclude other features, components, or steps. The disclosure in the abstract accompanying this application is incorporated herein as reference. Additional objects, advantages and features of the invention will be set forth in part in the description, and in part will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and they are not intended to be limiting the present invention.DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS

Problems solved by technology

It is well known that the benzimidazole compound has a poor stability over time.

In the solid state it is susceptible to moisture, light and heat, and in aqueous solution or suspension the stability decreases with decreasing pH.

As conventional enteric coatings are acidic, the need of protecting the pharmaceutical active ingredient from the enteric coating became an evident problem, as soon as the acid labile properties of the benzimidazole compound were known.

However, the choice of a particular combination of core and barrier layers in the pellet formulation, in order to provide both efficient manufacturing processes while maintaining a high degree of stability, remains a delicate matter.

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